Quinoline derivatives



Patented Feb. 25, 1947 UNITED STATES PATENT OFFICE QUINOLINE DERIVATIVES Frederick Robert Basford, Manchester, Harold.

Coates, Leeds, and Ian Morris Heilbron and Arthur Herbert Cook, London, England, assignorsfto Imperial Chemical Industries Limited, a corporation of Great Britain No Drawing. Application March 24, 1943, Serial No. 480,382. In Great Britain March 30, 1942 as make them valuable as medicinals. .Someof them are useful as s'pasmolytic agents. a n

We have now found that analogous new quincline derivatives having similar valuable properties may be obtained by carrying out the same reaction upon (1-, ,8- or -amlnophenylpyridines wherein thephenyl radical carries one or more of the following substituents, namely, bromo, iodo, alkyl of at least two carbon atoms, alkoxy of at least two carbon atoms, lhydroxy and aryloxy. but must have at least one of the positions ortho to the amino group free. These new compounds also are useful as spasmolytic agents.

According to the present invention, therefore, we, make new quinoline derivatives by a process which comprises treating an oz-, 5- or 'y-aminophenylpyridi-ne, wherein the phenyl radical carries one or. more oil thev following substituents, namely, bromo; iodo, alkyl' of "at least two carbon atoms, alkoxy of at least-two carbon-atoms, hydroxy. or aryloxy, but must -have at least one of the positions 'ortho to the "amino group free, with glycerol in the presence of an ox dising agent as further defined below and sulphuric acid,

. The aminophenylpyridines which are used. as starting materials may be made by reducing the corresponding nitrophenylnyridines, which themselves may conveniently be obtained by combin:

ing the diazo com ounds of the-appropriate nitro- 4 Claims. (01. 260-288) anilineswithpyridine bythe; method described I in-British Patent 518,886. The immediate products of this invention are frequently mixtures of isomeric nitrop'h'enyl w, and 'y-pyridines. The

reduction andseparately used as starting materials.

The oxidising agentslto'b e in the present invention are arsenic oxide, nitrobenzene, mail-y trobenzenesulphonic acid and other compcunds,

known to be suitable for use ascxidising agents in the Skraup synthesis of quinolines (for which see for example Houben Die Methoden der organischen Chemie, 3d Edt, Leipzig, 1925, vol. 2,1 g

p. 918'). I The following examples. illustrate, but do not limit, the invention. The parts are by weight. 4

r mble 1 v 12.5 parts of 3-amino-4-ethoxyphenylpyridine are mixed withlOO parts of 66% sulphuric acidQ- 19 parts of sodium m-nitrobenzenesulphonate and 14 parts of glycerol. The'mixture is gently boiled under a reflux condenser for 3 hours, after which I i it is diluted with Water and madealkaline with ammonia. The oil which separates out is extracted with benzene, the benzenelayer bei separated and dried. The 'benzeneiis distilled oif whereupon an oil remains. Q This is, 'c rude5 pyridyl-B-ethoxYquinoline (mixed oc-, 5- and '7'- isomers) and may be represented by-the formula the manner described in British Patent 5 18,886 and then nitrating and reducing the'nitro- COIIl-r pound so obtained.

Examplez I I 7.7 parts of. 3 -amino}4 phenoxyphenylpyridine (prepared by condensing the diazonium salt from 4-amino 2-acetylamino-diphenyl ether with pyridine according to the method of British Patent No. 518,886) I aremixed with 50 parts of66%. sulphuricacid, 7 parts of glycerine and 9.5 parts of sodium m-nitrobenzene sulphonate. Themixture is boiled under. reflux ior,4 hours.and is" then diluted with water and madealkaline with an monia. An oil separates outandisextracted with benzene. The benzene solutionis dried and the benzene is distilled off. ,An oil remains. This is acrude mixture of the isomeric 5 -pyridyl 8;

distils over maze-2 35? c. under 0.75 mm. presphenoxyqulnolines, which may be represented by the formula wherein Py has the same significance as above. Itis distilled under diminished pressure and the purified S-pyridyl-8-phenoxyquinoline fraction is collected at 250-280 C. at 0.25 mm. pressure. 7

Example 3 14.7 parts of 3bromo-4-aminopheny1pyridine (obtained by diazotising 2-bromo-4-amino-acetanilide and condensing with pyridine, followed'by' hydrolysis), 100 parts of 66% sulphuric acid, 14 parts of glycerol and 19 parts of sodium m-nitro-- benzene sulphonate are boiled'under reflux for 3 /2 hours. The mixture is diluted with water, made alkaline with ammonia,- and extracted with benzene. The benzene extract is dried and distilled. The fraction containing the mixed 8- bromo-6-pyridylquinolines 7 sure.

" Eramplest:

- 22 parts of 2-amino-4-tert-butyl-phenylpyridine, 146 parts of 64% sulphuric acid, 33.5 parts of glycerol, and 39 parts of sodium m-nitroben-v zene sulphonate are heated under reflux at 160 C. for 6 /2 hours. The solution is cooled and filtered and then made alkaline with ammonia. A tarry mass separatesout-"on standing. This is extracted with benzene. The extract is distilled and the fraction containing the mixed tertbutyl-8-pyridylquinolines is collected as a pale yellow oil B. P. 120 C. at 0.00002 mm. pressure. 7 I V The 2-amino-4-tert-butyl-phenylpyridine used as starting material is obtained by diazotising 3- nitro-4-amino-tert-butylbenzene' (for which see Gelzer, Berichte 1887, 20, 3257) and condensing with pyridine, and then reducing the product with stan nous chloride. and hydrochloric acid.

Example 5 V 2 partsni' a-(4-hydroxye3-aminophenyl) pyridine, 12 parts of 6.3% sulphuric acid, 2.4 parts of glycerol and 2 parts of sodium m-nitrobenzene sulphonate'are heated under reflux at'160" C. .f r '51 hours. The solution is cooled; diluted with 20 parts of water, filtered, and made faintly alkaline with sodium hydroxide solution. A brown precipitate is formed. This'is filtered oiT and extracted witlrf benzene and the extract is -clarified with charcoal. The benzene solution'is the evaporated down to small bulk and light petroleum is added. This .precipitates 8-hydroxy-5-(apyridyl) -quinoline which is filtered off and dried. It may be purified 'by sublimation in vacuo, when it yields colourless crystals M. P.-133.5134 C.

The a-(4-hydroxy 3 -'aminophenyl) -pyridine used as starting material is prepared from the corresponding u-(4-aminophenyl) -pyridine which is itself obtained by reduction of u-(4-nitrophenyD-pyridine (made by the method described in British Patent No. 518,886). The a-4-aminophenyD-pyridine is nitrated, boiled with caustic alkali to replace the NHz group by OH and then reduced." 7 'Weclaim: p

1. New 'pyridyl-quinolines of the formula wherein the pyridyl groupis attachedby any of its carbon atoms to any position in the phenyl ring of the quinolyl radical, said phenyl ring.

bearingalso at leastone substituent selected from the group consisting of bromo, iodo, butyl, eth0xy,'hydroxy and phenoxy.

2. Pyridyl quinolines of the formula:

tertwherein X stands for a'substituent selected from the group consisting ofbromo,iodo, tert butyl;

ethoxy, hydroxy and -phenoxy,'and wherein; the J REFERENCES crrEn I t The followingreferences are pf record in the e Q i .FOREIGN PATENTS OTHER REFERENCES:

Chem. Abstracts, vol. 29,- p'ag e" 69507; vol.' '30 page 41671. r a I Berichte, vol. 19, page 2475.

Hollins, Synthesis voi Nitrogen Ring Come pounds, D. Van Nostrand Co., N. Y., 1924, pages 245-50. '(CopyinDiv. 59.) i .1 Chem.'Soc. Jour. (London), 1943,.pags'401 406. (Copies inPat. 011;..Lib.) i I U. S. S. R1), yol. j9

Rubstov, J. Gen. Che "(1939).1). 1519.

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